Water vapor solid-state interactions are important in the pharmaceutical industry. These interactions are used to determine the “solid-state” stability of active pharmaceutical ingredients (API) or drug substances, finished products or drug products and raw material. Pharmaceutical solids may come in contact with water vapor during exposure upon handling and/or storage in an atmosphere of high relative humidity (RH). It is known that certain crystal forms, upon exposure to specific RH levels, convert to a different crystal form by a process known as moisture mediated crystallization. This process is especially problematic for the pharmaceutical industry as the crystal form conversion may result in a reduced shelf-life of a drug product. More importantly, the resulting converted crystal form may have different physical properties such as greater stability, reduced solubility, and hence may be less bioavailable compared to the starting or initial crystal form.
Moisture sorption gravimetry (MSG), also known as a “moisture sorption microbalance,” is a widely used conventional technique that employs a microbalance in a sealed chamber at known RH levels to study water vapor solid-state interaction by measuring the sample's weight gain or loss at various RH levels. A complete cycle includes a sorption cycle from 0 to about 95% RH and desorption cycle from about 95% to 0% RH, and may take up to a few days to finish. The solid-state stability data may be estimated from isotherms generated by plotting the solid's moisture content over an RH range. The solid-state stability data may then be used to estimate shelf life and storage conditions of the API. While MSG is known as a useful technique to determine moisture content of a solid over a wide RH range, the analyst generally employs solid-state techniques to identify the crystal forms of a solid over the same RH range.
An important consideration in determining which crystal form to formulate and market is the water vapor solid-state stability. Typically, the least hygroscopic crystal form, or with the least water vapor solid-state interaction is chosen to be formulated in the marketed product. The identification of suitable solid-state phases or crystal forms is achieved by exposing samples in different relative humidity (RH) chambers over a period of time. The exposed samples are then removed from the RH chambers and then analyzed by conventional solid-state techniques, such as x-ray powder diffraction (XRPD) and mid-infrared (IR) spectroscopy to determine if any changes in the solid-state phase or crystal form had occurred in the various samples. However, these solid-state techniques have many disadvantages. Firstly, they are very time consuming, often taken up to a month to complete a RH exposure study from about 10 to 90% RH. Secondly, the techniques used require that the sample be manipulated first, such as grinding with a mortar and pestle for XRPD experiments, and grinding with potassium bromide for IR samples. Overgrinding crystalline samples has been known to change from the solid's solid-state phase to an amorphous phase, and hence may not be representative of the sample under investigation. Furthermore, an XRPD experiment may take up to about 45 minutes to complete, while the sample is exposed to ambient RH levels. During such exposure, the state or degree of hydration of the sample may change, particularly if the was initially exposed to RH levels different from ambient levels. IR experiments also have similar problems. Typically, ground IR samples are first placed in a nitrogen purged or desiccated atmosphere before an IR spectrum can be obtained. Placement of the sample in such an environment may change its state of hydration during the experiment and will not be representative of the water content or degree of hydration at the exposed RH levels. Thirdly, a complete RH exposure study requires a relatively large amount of sample that may be consumed by additional solid-state studies. For XRPD experiments, for instance, large amounts of sample (about 200-300 mg) is required for a good diffraction pattern. This is problematic when only minute samples (about 1 mg) are involved.
Near infrared spectroscopy (NIRS) is widely recognized as a technique to study solid-state phases or crystal forms of the same API. NIRS can degree of hydration. NIRS uses the part of the electromagnetic spectrum between the visible and the mid infrared (mid-IR), typically between 800 to 2500 nm. NIR spectra are produced by utilizing the combination bands and overtones of the mid-IR fundamental absorption bands. Combination bands are the result of the mathematical addition of mid-IR fundamental bands. Overtones are the harmonics of the mid-IR fundamental bands. Since combination bands and overtones are typically 10 to 100 times smaller than mid-IR fundamental bands, no sample dilution is required, and little or no sample preparation is necessary, making NIRS an ideal technique in analyzing solid-state samples. Moreover, the total time of a typical NIR analysis may be as little as a few seconds.
Raman spectroscopy, unlike mid and near-infrared absorption spectroscopy, is a light scattering process in which the sample is irradiated with intense monochromatic light, usually laser light; and the light scattered from the sample is analyzed for frequency shifts in the range of about 4000 to 25 wavenumbers (cm−1). Inelastic light scattering of monochromatic light with a sample generates Raman spectra.
In general, the Raman spectrum and the mid-infrared spectrum provide similar data, although the intensities of the spectra are produced by different molecular properties. Raman and mid-infrared spectroscopy exhibit different relative sensitivities for different functional groups, for example, Raman spectroscopy is particularly sensitive to C—S and C—C multiple bonds. In addition some aromatic compounds are more easily identified by their Raman spectra. Furthermore, symmetric vibrations and non-polar functional groups produce the most intense Raman bands. This is in contrast to mid-infrared spectroscopy where antisymmetric vibrations and polar groups produce strong absorption bands. Since Raman spectroscopy has bands in known spectra-structure correlations, it provides a direct probe of the molecular structure of a sample. Like NIR, little or no sample preparation is required for Raman analysis. Sampling could also be performed with fiber optic probes since the laser light used in Raman spectroscopy is in the near-infrared region. Water has highly intense mid- and near-infrared absorption spectra, but a particularly weak Raman spectrum, making water a Raman transparent solvent for aqueous sample analysis and solute identification and quantification.
While NIRS and Raman spectroscopy have a number of advantages that surpass the use of XRPD or mid-IR as general techniques for analyzing solid-state phase or crystal form changes as a function of RH, the analyst must still remove the sample from the RH chamber to perform NIRS or Raman, thus exposing the sample to ambient RH. Therefore, there may be no correlation to the solid-state phase at a certain RH in the MSG experiment and solid-state phase of the sample after removal from the MSG apparatus and subsequent exposure to ambient conditions.
Accordingly, there is a need in the art for a method and apparatus that allows for the accurate measurement of moisture content and solid-state phase of a sample that avoids many of the aforementioned disadvantages of conventional methods. A method and apparatus that would allow the simultaneous or contemporaneous measurement of moisture content and solid-state phase of a sample without the removal of the sample from a controlled environment would be highly desirable.